Dramatic progress has been made in recent years identifying mutational events in tumor cells that[unreadable] lead to progression to the malignant phenotype. However, it has become apparent that the full[unreadable] expression of this malignant phenotype is modulated by the tumor microenvironment. In breast[unreadable] cancers, the topic of this application, this consists of many cell types including fat cells, fibroblasts[unreadable] and immune cells. In the latter class, macrophages are notable in their abundance and in clinical[unreadable] studies an increase in their density is correlated with poor prognosis. Research by the PI has shown[unreadable] that these macrophages play important roles in tumor progression and metastasis. These and[unreadable] others studies have led us to propose six separate traits whereby macrophages can promote tumor[unreadable] progression and metastasis. These are chronic inflammation, matrix remodeling, tumor cell[unreadable] invasion, intravasation, angiogenesis and seeding at distant sites. This led to the hypothesis that[unreadable] the tumor microenvironment educates macrophages to perform specific tasks. Nevertheless, in[unreadable] other contexts macrophages can kill tumor cells and present antigens to cytotoxic T cells. This has[unreadable] led to the concept that tumors evolve to avoid immune destruction and to enhance the trophic roles[unreadable] of these immune cells. In this proposal in three projects, in human breast cancers and mouse[unreadable] models we will define the mechanistic interactions between tumor cells, the immune system and[unreadable] other components of the microenvironment that results in tumor progression and metastasis.[unreadable] Project 1: Natural History of immune responses in a mouse model of spontaneous breast[unreadable] cancer. This addresses the hypothesis that the tumor microenvironment biases the local immune[unreadable] response away from a cytotoxic one to a benign or trophic one through the recruitment of regulatory[unreadable] T cells and myeloid cells. Project 2; The role of macrophages in breast cancer angiogenesis.[unreadable] This will define the mechanism that macrophages employ to enhance angiogenesis in the tumor.[unreadable] Project 3: Novel Methods for Detecting Cell Interactions in the Tumor Microenvironment.[unreadable] This uses nanotechnology to miniaturize an artificial blood vessel that can in dwell in human tumor[unreadable] xenografts and ultimately in human tumors that can report on the status of cell collection and[unreadable] diagnose invasive tumors.[unreadable]